NL-4 IN AUTISM
Investigating the role of Neuroligin-4 in the development of autism-related synaptic and behavioral abnormalities in mice
| Coordinatore | MAX PLANCK GESELLSCHAFT ZUR FOERDERUNG DER WISSENSCHAFTEN E.V.
Organization address
address: Hofgartenstrasse 8 contact info |
| Nazionalità Coordinatore | Germany [DE] |
| Totale costo | 100˙000 € |
| EC contributo | 100˙000 € |
| Programma | FP7-PEOPLE
Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) |
| Code Call | FP7-PEOPLE-2010-RG |
| Funding Scheme | MC-IRG |
| Anno di inizio | 2010 |
| Periodo (anno-mese-giorno) | 2010-10-01 - 2014-09-30 |
Partecipanti
| # | ||||
|---|---|---|---|---|
| 1 |
MAX PLANCK GESELLSCHAFT ZUR FOERDERUNG DER WISSENSCHAFTEN E.V.
Organization address
address: Hofgartenstrasse 8 contact info |
DE (MUENCHEN) | coordinator | 100˙000.00 |
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Obiettivo del progetto (Objective)
'Autism is a frequent neurodevelopmental disorder, characterized by impairments in social interaction, language deficits, and repetitive behaviors. The biological basis of autism remains unknown, and no cure or effective pharmacological treatment is currently available. Given the high prevalence of autism and the devastating consequences for patients and families, it is essential to improve our understanding of the molecular mechanisms underlying autism and to identify potential therapeutic approaches. According to an important new concept that has arisen over recent years, autism may be a ‘synaptopathy’, i.e. a disorder resulting from an aberrant development and function of synaptic connections in the brain. In support of this hypothesis, autism-related mutations have recently been identified in a number of proteins that play an essential role at synapses. In particular, several different mutations in the synaptic adhesion molecule Neuroligin-4 (NL-4) have been linked to autism, making this one of the most frequent monogenic causes of non-syndromic autism known to date. However, little is known about the molecular mechanisms by which NL-4 affects synapse development, or how loss of function of NL-4 may lead to the cognitive and behavioral impairments characteristic of autism. Here, we propose to address this issue by investigating the effects of constitutive and inducible manipulations of the NL-4 gene in mice, using a combination of molecular, physiological, and behavioral techniques. This approach will allow for a detailed characterization of the role of NL-4 in synapse formation and maintenance. This, in turn, will enable us to elucidate the relationship between NL-4-induced synaptic abnormalities and autism-related behaviors. Our study will greatly contribute to the understanding of the role of synaptic proteins in the pathogenesis of autism, and will generate important animal models for the development and validation of potential therapeutic strategies.'
Introduzione (Teaser)
Autism spectrum disorders (ASDs) are neurodevelopmental disorders affecting tens of millions globally with no currently available effective cure. EU-funded researchers have demonstrated a link between synaptic proteins and autism-related behaviour.
Descrizione progetto (Article)
Individuals with ASD lack social skills, show behavioural changes, and often exhibit poor verbal and non-verbal communication. To find a cure or prevent ASD onset, it is necessary to elucidate the underlying molecular mechanisms.
Neuroligins (NLs) are synaptic cell adhesion proteins that mediate synapse development and function. Genetic mutations affecting NL4 in particular have been linked to ASD. Researchers of the NL-4 IN AUTISM project investigated the role of NL4 in ASDs as well as synapse development and function using NL4 knockout (KO) mouse models.
To begin with, researchers identified areas of the brain where NL4 is widely expressed. They focused on the hippocampal region and found that loss of NL4 affects synapses involved in processing cognitive information that helps in guiding behaviour. Proteomic screening of NL4 KO mice helped identify several proteins with altered expression.
A major achievement is the development of novel conditional NL KO mouse models. These models can be used for testing effects of NL expression or loss at different time intervals during postnatal brain development. Such conditional expression should help reveal if it is possible to reverse cognitive impairments.
Project activities have opened up novel avenues for developing therapies for ASDs. The NL4 KO mouse models will prove particularly useful in studying neurodevelopmental disorders and identifying autism-related behavioural phenotypes. Future studies could reveal if ASDs and cognitive impairment can be reversed through treatment.